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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2118-2123 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.2090 Potential Regional Differences for the Tolerability Profiles of Fluoropyrimidines
From the Abramson Cancer Center at the University of Pennsylvania, Philadelphia; NSABP Foundation, Pittsburgh, PA; University of Texas, M.D. Anderson Cancer Center, Houston, TX; Vanderbilt-Ingram Cancer Center, Nashville, TN; Memorial Sloan-Kettering Cancer Center, New York; Roswell Park Cancer Institute, Buffalo, NY; NCI-Navy Medical Oncology Branch, National Cancer Institute, Bethesda, MD; The Cancer Institute of New Jersey, New Brunswick, NJ; Glasgow University, Glasgow; Royal Marsden Hospital, London; University of Leeds and Bradford NHS Trust, Bradford, United Kingdom; University of Sydney and Sydney Cancer Centre, Sydney, Australia; University Hospital Gasthuisberg, Leuven, Belgium; Martin Luther University, Halle, Germany; Centre René Gauducheau, St Herblain; Centre Antoine-Lacassagne, Nice, France; Gothenburg University, Gothenburg, Sweden; Vall d'Hebron University Hospital, Barcelona, Spain; and F. Hoffmann-La Roche, Basel, Switzerland Corresponding author: Chris Twelves, MD, Cancer Research UK Clinical Centre, St James University Hospital, Beckett St, Leeds, LS9 7TF United Kingdom; e-mail: c.j.twelves{at}leeds.ac.uk; or c.twelves{at}bradford.ac.uk
Purpose We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability. Methods Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study). Results In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR. Conclusion Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.
Fluorouracil (FU) is one of the most active single agents for the treatment of metastatic colorectal cancer (MCRC).1-3 To compensate for the relatively short half-life of FU and to increase its activity, modified dose schedules and combinations with biochemical modulators, such as leucovorin (LV), have been used.2-4 When administered by repeated intravenous (IV) bolus injections or short infusions, FU is associated with a number of adverse effects, particularly gastrointestinal (including diarrhea and stomatitis) and bone marrow toxicity.5 Findings from direct comparisons of infusional schedules (de Gramont) compared with bolus FU regimens in MCRC6 and in the adjuvant setting7 showed improved safety with infusional FU. Infusional FU is associated with the need for a permanent indwelling catheter, which can lead to complications and is inconvenient for the patient.8 Although acute toxicity is less severe with continuous infusions, other adverse effects, such as hand-foot syndrome (HFS), become more apparent.5,9,10 Capecitabine (Xeloda; F. Hoffmann La-Roche, Basel, Switzerland) is an oral fluoropyrimidine prodrug. In first-line therapy for MCRC, capecitabine has shown improved response rates and equivalent time to disease progression and overall survival compared with the contemporaneous standard bolus Mayo Clinic FU/LV regimen, and a more favorable safety profile.11-14 Similar efficacy to bolus FU/LV has also been seen when capecitabine is administered as adjuvant therapy for stage III colon cancer.15 In MCRC and the adjuvant colon cancer setting, capecitabine was associated with less neutropenia and stomatitis but more HFS compared with bolus FU/LV.11-14,16 In combination with oxaliplatin, a recent analysis of a randomized 2 x 2 factorial phase III trial has shown that capecitabine-based therapy (XELOX) with or without bevacizumab is noninferior to FOLFOX-4 with or without bevacizumab in terms of progression-free survival in first-line MCRC.17 In addition, the comparable safety of XELOX versus IV bolus FU/LV has recently been confirmed in the adjuvant setting.18 Despite the proven safety profile of capecitabine in clinical trials, conflicting opinions have been voiced by clinicians in Europe and the United States (US) regarding the tolerability of the approved dose of capecitabine (1,250 mg/m2 twice per day on days 1 through 14 every 3 weeks). In Europe, the approved dose appears to have acceptable tolerability and is widely used, whereas market research data indicates that, in the US, clinicians tend to use a lower dose (1,000 mg/m2 twice per day; Fig A1 online only; data on file, F. Hoffmann La-Roche). There is currently limited published information on regional differences in fluoropyrimidine tolerability. Safety data from the International Multicentre Pooled Analysis of Colon Cancer Trials analysis, and other observations, suggest a difference in reported toxicity for patients receiving adjuvant bolus FU/LV in the Gruppo Interdisciplinare Valutazione Interventi Oncologia and the National Cancer Institute of Canada Clinical Trials Group studies.19 These lines of evidence led to the hypothesis that there might be regional differences in the patient tolerability profiles of fluoropyrimidines. In order to investigate these potential differences further, we conducted a retrospective analysis of safety data from three phase III trials comparing IV bolus FU/LV with capecitabine with or without oxaliplatin in either the metastatic12,13 or adjuvant settings.18 This analysis does not compare capecitabine with infusional FU regimens.
This retrospective multivariate analysis used data from three phase III clinical studies: two identical studies (SO14796 and SO14695), which compared capecitabine (n = 596) with the Mayo Clinic regimen of IV bolus FU/LV (n = 593) for MCRC12,13; and an adjuvant study (NO16968; XELOXA) in stage III colon cancer, which compared capecitabine plus oxaliplatin (XELOX, n = 938) with IV bolus FU/LV (n = 926), given as either the Mayo Clinic or Roswell Park regimen.18 End points included progression-free survival in the MCRC studies, disease-free survival in the adjuvant study, and overall survival and tolerability in all three studies. Study design details are shown in online-only Figures A2A and A2B. The pooled SO14796/SO14695 studies in MCRC and NO16968 in adjuvant colon were analyzed separately. The NCIC CTC (version 1) toxicity scale was employed in the SO14796 and SO14695 studies and, in the NO16968 study, the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 3) was used. Treatment-related safety parameters evaluated were grade 3/4 adverse events (AEs), serious adverse events (SAEs), grade 3/4 gastrointestinal AEs (diarrhea, nausea, vomiting, and stomatitis events), grade 3/4 neutropenia events (neutropenia/granulocytopenia and febrile neutropenia), grade 3/4 reductions in neutrophil counts, dose reductions (yes/no) and treatment discontinuations (yes/no). In practice most SAEs (as defined in International Conference on Harmonisation guidelines) were AEs resulting in hospitalization. In all three studies, creatinine clearance was calculated using the Cockroft-Gault formula. The US was compared with non-US countries in all three studies. In addition, in the adjuvant study NO16968, the US was compared with East Asian countries and with countries in the rest of the world outside US and East Asia, mainly Europe (rest of the world). Data were analyzed by multivariate analysis (logistic regression) to identify safety parameters associated with regional differences. The model was adjusted for age, sex, body mass index (BMI), body-surface area (BSA), baseline creatinine clearance, Eastern Cooperative Oncology Group performance status, and treatment (bolus FU/LV, capecitabine, capecitabine/oxaliplatin). Relative risks and their 95% CIs were reported. An interaction term between region and treatment was included in the model. Interaction was assessed at a P value of .05. If the interaction term was significant in the adjusted model, the stratified relative risks by treatment were compared. If no significant interaction was detected, it was concluded that the model adjusted for baseline factors and treatment arm performed properly and that the relative risk indicating a regional difference in safety parameters applied to fluoropyrimidine treatment regardless of the regimen used. If an interaction by region was detected, it was concluded that the model adjusted for treatment did not perform properly and an analysis of relative risks by treatment arm was conducted. This was also a multivariate analysis adjusted for baseline factors but not by treatment. For HFS, the low incidence in the FU group precluded the use of the statistical model. Therefore, only a descriptive approach was used for capecitabine.
Baseline Characteristics: US Versus Non-US Patients The following numerical (not significant) differences concerning baseline characteristics were observed (Appendix Tables A1, A2, and A3, online only). In the MCRC studies (n = 1,189), US patients had a slightly higher median BSA and slightly higher creatinine clearance rates compared with non-US patients. In the adjuvant colon cancer study (n = 1,864), patients in Asia were slightly younger and had a lower median BMI and BSA than those in the US and the rest of the world. US patients had a slightly higher BSA and BMI than those patients in the rest of the world and East Asia. Creatinine clearance rates were also slightly higher in US patients compared with those in the rest of the world and East Asia.
Analysis in First-Line MCRC: US Versus Non-US Patients
Analysis in Adjuvant Colon Cancer: US Versus the Rest of the World and Asia Differences in the rates of treatment-related AEs were also observed in patients receiving adjuvant therapy (Table 3). According to multivariate analysis, significantly more grade 3/4 AEs, grade 4 AEs, and discontinuations were reported in US compared with non-US patients (Table 4). The analyses were repeated dividing the non-US patients into those in East Asia and the rest of the world (Table 5). An increase in the relative risk for related grade 3/4 AEs, grade 4 AEs, grade 3/4 gastrointestinal AEs and SAEs, grade 3/4 neutropenia events, and discontinuations was observed with East Asian patients having the lowest and US patients the highest relative risk. This differential in reported toxicities in East Asia compared to the US was neither observed for laboratory neutrophil counts nor for dose reductions (Table 5).
Analysis of Interactions Significant interactions between region and the type of fluoropyrimidine treatment (Mayo Clinic or Roswell Park regimen) were observed for grade 3/4 neutropenia events and grade 3/4 laboratory neutrophils counts (Table 4). In both cases, the significant interactions were due to regional distribution in the use of the Mayo Clinic versus Roswell Park regimen in the bolus FU/LV arm in the adjuvant NO16968 study. Whereas most of the patients treated in the US received the Roswell Park regimen, most patients outside the US received the Mayo Clinic regimen. A contributing factor was neutropenia being a very common AE for the Mayo Clinic regimen. A stratified analysis by treatment showed that the Mayo Clinic regimen was indeed responsible for the difference (Table 4). The incidence of grade 3 HFS was clearly higher in US compared with non-US patients in the adjuvant setting with capecitabine plus oxaliplatin (study NO16968, Table 3), but not in the metastatic setting with monotherapy (Table 1).
This retrospective analysis shows that regional differences exist in the reported tolerability profiles of IV bolus FU/LV and oral capecitabine, which may not only represent differences in reporting but also real differences in tolerability. These findings have implications both for the regulatory approval process and the use of drugs in routine clinical practice. The Department of Health and Human Services in the US issued a general guidance in 1998 on ethnic factors that can potentially be underlying causes for regional differences in drug effects,20 recommending regulatory and development strategies to permit clinical data collected in one region to be used for the support of drug and biologic registrations in another region while allowing for the influence of ethnic factors. Potential ethnic factors that could be underlying causes for regional differences in drug effects can be either intrinsic, such as genetic polymorphisms and physiological or pathological conditions, or extrinsic, such as cultural differences, dietary habits, and differences in clinical trial methodology. A number of factors may give a spurious impression of regional variation in treatment tolerability. Reporting bias in the recording of AEs by investigators might be one such factor. Differential reporting of toxicities by patients from different racial groups could also be factor. For example, McCollum et al21 showed that African American patients experienced significantly less treatment-related toxicity than white patients after FU-based adjuvant chemotherapy in colon cancer. Differences in age, sex, BMI, BSA, baseline creatinine clearance, and Eastern Cooperative Oncology Group performance status could also lead to apparent geographical variation in toxicity. For example, dosing of both FU and capecitabine is based on BSA, which is influenced by weight. Renal function also affects the tolerability of fluoropyrimidines. In two randomized studies of bolus IV FU/LV and capecitabine in MCRC, there was an increased incidence of toxicity in patients with moderate renal impairment.11 This analysis was, however, adjusted for all these baseline factors. Another potential reason for the regional disparities in the safety profile of fluoropyrimidines might be differences in dietary folate intake.22 The mechanism of action of fluoropyrimidines is dependent on the presence of folates because binding of the FU metabolite fluorodeoxyuridine monophosphate to the enzyme thymidylate synthase is stable only in the presence of reduced folate (N5,N10-methylenetetrahydrofolate). A relationship between dietary folate intake and the efficacy and safety of fluoropyrimidines is supported by preclinical data. In a breast cancer xenograft model, FU-treated rats fed a high folate diet had improved tumor responses and prolonged survival compared with those on a low folate diet.23 However, FU toxicity was increased significantly in rats receiving the high folate diet.24 Clinical studies have also suggested a relationship between dietary folate and fluoropyrimidine toxicity.25,26 In one study, patients receiving adjuvant bolus FU/LV (Mayo Clinic regimen) were assessed prospectively for biomarkers of folate metabolism. Multivariate analyses identified baseline serum folate as an independent predictor of grade 3/4 toxicity or dose modification (P = .016).25 Similar results were found in a study of capecitabine monotherapy (2,000 mg/d flat dose on an intermittent schedule) in which patients with higher baseline levels of serum folate had significantly increased toxicity levels (P = .005).26 Cultural differences in patients’ behavior are a potential factor for oral self-administered drugs. For example, some patients may be more likely to continue treatment despite experiencing adverse effects and despite any information they may have been provided with informing them about potential toxicity. However, the same patterns of regional variability were seen for bolus FU as for oral capecitabine. Cultural differences in medical practice, such as the time available for providing patients with information about their treatment, the availability of medical staff when adverse effects occur, and how well sponsors have trained investigators and prescribing physicians about safety and adverse effects, may also play a role. Genetic polymorphisms for genes involved in fluoropyrimidine metabolism may be important from the perspective of both the individual patient and a homogenous ethnic group. However, genetic polymorphisms are unlikely to provide an explanation in populations that are genetically very heterogeneous, such as in the US, having significantly different tolerability of fluoropyrimidines compared with other areas of the world. In conclusion, regional differences exist in the reported tolerability profiles of fluoropyrimidines in general, rather than in relation to any specific drug (ie, bolus FU or capecitabine). More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV or capecitabine in the first-line treatment of MCRC and for bolus FU/LV or capecitabine plus oxaliplatin in the adjuvant treatment of colon cancer. In the adjuvant setting, a clear range of fluoropyrimidine tolerability was observed, with patients from East Asia having the lowest and US patients the highest relative risk. Further evaluation of these regional differences should be undertaken as part of ongoing clinical trials to establish optimal regimens for diverse populations, and other retrospective studies should be performed to further explore potential causes for regional differences in the tolerability of fluoropyrimidines. However, based on our preliminary observations, although no recommendations for individual dosing in specific regions can be made, an awareness of regional differences in reported tolerability profiles may facilitate drug development in phases I and II.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Florin Sirzén, F. Hoffmann-La Roche Ltd (C) Consultant or Advisory Role: Daniel G. Haller, Roche (C), Sanofi-aventis (C); Jim Cassidy, Roche (C); Stephen J. Clarke, Colorectal Advisory Board (C); David Cunningham, Roche (C), Sanofi-aventis (C); Eric Van Cutsem, Roche (C); Paulo M. Hoff, Roche (C); Mace L. Rothenberg, Roche (C); Hans-Joachim Schmoll, Roche (C); Carmen Allegra, Roche (U); Jean-Yves Douillard, Roche (C); Gerard Milano, Amgen (C); Michael O'Connell, Roche (C); Josep Tabernero, Roche (C); Chris Twelves, Roche (C) Stock Ownership: None Honoraria: Daniel G. Haller, Roche, Sanofi-aventis; Jim Cassidy, Roche; David Cunningham, Roche, Sanofi-aventis; Paulo M. Hoff, Roche; Hans-Joachim Schmoll, Roche; Jean-Yves Douillard, Roche; Gerard Milano, Roche; Josep Tabernero, Roche; Chris Twelves, Roche Research Funding: Daniel G. Haller, Roche; Jim Cassidy, Roche; David Cunningham, Roche, Sanofi-aventis; Eric Van Cutsem, Roche; Paulo M. Hoff, Roche; Mace L. Rothenberg, Roche; Leonard B. Saltz, Roche, Genentech; Gerard Milano, Roche, AstraZeneca, Pfizer; Josep Tabernero, Roche Expert Testimony: David Cunningham, Roche (U) Other Remuneration: None
Conception and design: Daniel G. Haller, Jim Cassidy, Eric Van Cutsem, Mace L. Rothenberg, Hans-Joachim Schmoll, Carmen Allegra, Bengt G. Gustavsson, Michael O'Connell, Josep Tabernero, Frank Gilberg, Florin Sirzén, Chris Twelves Financial support: Florin Sirzén Administrative support: Florin Sirzén Provision of study materials or patients: Jim Cassidy, Eric Van Cutsem, Paulo M. Hoff, Mace L. Rothenberg, Leonard B. Saltz, Hans-Joachim Schmoll, Bengt G. Gustavsson, Chris Twelves Collection and assembly of data: Mace L. Rothenberg, Florin Sirzén Data analysis and interpretation: Daniel G. Haller, Jim Cassidy, Stephen J. Clarke, David Cunningham, Eric Van Cutsem, Paulo M. Hoff, Mace L. Rothenberg, Hans-Joachim Schmoll, Carmen Allegra, Joseph R. Bertino, Jean-Yves Douillard, Bengt G. Gustavsson, Gerard Milano, Michael O'Connell, Youcef Rustum, Josep Tabernero, Frank Gilberg, Florin Sirzén, Chris Twelves Manuscript writing: Daniel G. Haller, Jim Cassidy, Stephen J. Clarke, Eric Van Cutsem, Mace L. Rothenberg, Hans-Joachim Schmoll, Carmen Allegra, Bengt G. Gustavsson, Gerard Milano, Michael O'Connell, Josep Tabernero, Frank Gilberg, Florin Sirzén, Chris Twelves Final approval of manuscript: Daniel G. Haller, Jim Cassidy, Stephen J. Clarke, David Cunningham, Eric Van Cutsem, Paulo M. Hoff, Mace L. Rothenberg, Leonard B. Saltz, Hans-Joachim Schmoll, Carmen Allegra, Joseph R. Bertino, Jean-Yves Douillard, Bengt G. Gustavsson, Michael O'Connell, Josep Tabernero, Frank Gilberg, Florin Sirzén, Chris Twelves
Supported by Roche. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006 and the 8th World Congress of Gastrointestinal Cancer, Barcelona, Spain, June 28 to July 1, 2006. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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J Clin Oncol 7:425-432, 1989[Abstract] 6. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997 7. André T, Quinaux E, Louvet C, et al: Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: Final results of GERCOR C96.1. J Clin Oncol 25:3732-3738, 2007 8. Verso M, Agnelli G: Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 21:3665-3675, 2003 9. Hansen RM: 5–Fluorouracil by protracted venous infusion: A review of recent clinical studies. Cancer Invest 9:637-642, 1991[Medline] 10. Mori A, Bertoglio S, Guglielmi A, et al: Activity of continuous-infusion 5-fluorouracil in patients with advanced colorectal cancer clinically resistant to bolus 5-fluorouracil. Cancer Chemother Pharmacol 33:179-180, 1993[CrossRef][Medline] 11. Cassidy J, Twelves C, Van Cutsem E, et al: First-line oral capecitabine therapy in metastatic colorectal cancer: A favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 13:566-575, 2002 12. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001 13. Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097-4106, 2001 14. Van Cutsem E, Hoff PM, Harper P, et al: Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: Integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 90:1190-1197, 2004[CrossRef][Medline] 15. Twelves C, Wong A, Nowacki M, et al: Capecitabine as adjuvant therapy for stage III colon cancer. N Engl J Med 352:2696-2704, 2005 16. Scheithauer W, McKendrick J, Begbie S, et al: Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: Safety results of a randomized, phase III trial. Ann Oncol 14:1735-1743, 2003 17. Cassidy J, Clarke S, Diaz-Rubio E, et al: XELOX compared to FOLFOX4: Survival and response results from XELOX-1/ NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC). J Clin Oncol 25:18s, 2007 (suppl; abstr 4030) 18. Schmoll HJ, Cartwright T, Tabernero J, et al: Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: A planned safety analysis in 1,864 patients. J Clin Oncol 25:102-109, 2007 19. Anon: Efficacy of adjuvant fluorouracil and folinic acid in colon cancer: International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 345:939-944, 1995[CrossRef][Medline] 20. Department of Health and Human Services, Food and Drug Administration: International Conference on Harmonisation: Guidance on ethnic factors in the acceptability of foreign clinical data; availability. Federal Register 63:31790-31796, 1998[Medline] 21. McCollum AD, Catalano PJ, Haller DG, et al: Outcomes and toxicity in African-American and Caucasian patients in a randomized adjuvant chemotherapy trial for colon cancer. J Natl Cancer Inst 94:1160-1167, 2002 22. Lewis CJ, Crane NT, Wilson DB, et al: Estimated folate intakes: Data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am J Clin Nutr 70:198-207, 1999 23. Branda RF, Nigels E, Lafayette AR, et al: Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats. Blood 92:2471-2476, 1998 24. Branda RF, Chen Z, Brooks EM, et al: Diet modulates the toxicity of cancer chemotherapy in rats. Lab Clin Med 140:358-368, 2002[CrossRef] 26. Ho C, Vincent M, Jonker D, et al: Folate, SAH, and SAM levels and the risk of severe toxicity in colorectal cancer patients treated with 5-FU and folinic acid. ASCO Gastrointestinal Cancers Symposium, January 22-24, 2004, San Francisco, CA (abstr 216) 27. Sharma R, Rivory L, Beale P, et al: A phase II study of fixed-dose capecitabine and assessment of predictors of toxicity in patients with advanced/metastatic colorectal cancer. Br J Cancer 94:964-968, 2006[CrossRef][Medline] Submitted November 5, 2007; accepted December 21, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
